A kind of 4-pyrimidinecarboxamide compound, pharmaceutical composition, preparation method and application

A compound and pharmaceutical technology, applied in the field of biomedicine, can solve problems such as reducing the rate of adverse reactions, inability to distinguish tumor cells, and side effects

Active Publication Date: 2020-09-08
北京鑫开元医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional cytotoxic drugs cannot distinguish between tumor cells and normal cells, often leading to serious side effects. Targeted drugs use tumor cells as specific targets, can accurately act on tumors, and can effectively improve the treatment level of cancer. Reduce adverse reaction rate

Method used

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  • A kind of 4-pyrimidinecarboxamide compound, pharmaceutical composition, preparation method and application
  • A kind of 4-pyrimidinecarboxamide compound, pharmaceutical composition, preparation method and application
  • A kind of 4-pyrimidinecarboxamide compound, pharmaceutical composition, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 6-((2-Hydroxy-2-methylpropyl)amino)-2-(3-oxo-4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidine-4 -Formamide

[0046]

[0047] first step:

[0048] Compound 1a (38.2g, 200.0mmol), compound 1b (17.8g, 200.0mmol), K 2 CO 3 (30.4g, 220.0mmol) was dissolved in DMF (400ml), and reacted at 60°C for 8 hours, and the reaction was detected by thin layer chromatography (Thin Layer Chromatography, abbreviated as TLC). After the reaction was completed, water (300ml) was added, and ethyl acetate ( 300ml) extracted twice, the organic layer was dried, concentrated and separated by chromatography to obtain 40.3g of compound 1c with a yield of 82.6%. Compound 1c was an off-white solid.

[0049] Step two:

[0050] Compound 1c (2.4g, 10.0mmol), compound 1d (2.4g, 10.0mmol), palladium acetate (122mg, 0.5mmol), triphenylphosphine (262mg, 1.0mmol), cesium carbonate (3.9g, 12.0mmol) Dissolve in DMF (50ml), then raise the temperature to 100°C and stir for 8 hours, TLC detects the r...

Embodiment 2

[0052] 2-(4-(3-aminocarbonylphenyl)-3-oxopiperazin-1-yl)-6-((2-hydroxy-2-methylpropyl)amino)pyrimidine-4-carboxamide

[0053]

[0054] Compound 1c was synthesized according to the method in the first step of Example 1.

[0055] Compound 1c (2.4g, 10.0mmol), compound 2a (2.2g, 10.0mmol), palladium acetate (122mg, 0.5mmol), triphenylphosphine (262mg, 1.0mmol), cesium carbonate (3.9g, 12.0mmol) Dissolve in DMF (50ml), then raise the temperature to 100°C and stir for 8 hours, TLC detects the reaction, after the reaction is completed, quench the reaction with water (40ml), then extract twice with ethyl acetate (50ml), and obtain by organic column chromatography 2.3 g of light yellow solid, yield 53.9%, ESI(+) m / z=428.2.

Embodiment 3

[0057] 6-((2-Hydroxy-2-methylpropyl)amino)-2-(3-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)pyrimidine- 4-Formamide

[0058]

[0059] Compound 1c was synthesized according to the method in the first step of Example 1.

[0060] Compound 1c (2.4g, 10.0mmol), compound 3a (2.6g, 10.0mmol), palladium acetate (122mg, 0.5mmol), triphenylphosphine (262mg, 1.0mmol), cesium carbonate (3.9g, 12.0mmol) Dissolve in DMF (50ml), then raise the temperature to 100°C and stir for 8 hours, TLC detects the reaction, after the reaction is completed, quench the reaction with water (40ml), then extract twice with ethyl acetate (50ml), and obtain by organic column chromatography 3.0 g of light yellow solid, yield 64.2%, ESI(+) m / z=469.2.

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Abstract

The invention belongs to the technical field of biological medicines, and provides a 4-pyrimidinecarboxamide compound, a pharmaceutical composition, a preparation method and an application. The 4-pyrimidinecarboxamide compound is a compound with a structure as shown in a formula I which is described in the specification, a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate and isotope compound thereof. In the formula I, R1 represents methoxyethyl, 2-amino-2-oxoethyl or 2-hydroxy-2-methylpropyl; and R2 represents a substituted or unsubstituted benzene ring or aromatic heterocycle. The 4-pyrimidinecarboxamide compound can be used as an effective IDH inhibitor; meanwhile, the pharmaceutical composition of the 4-pyrimidinecarboxamide compound has a variety of good anti-tumorpharmacological activity.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a 4-pyrimidinecarboxamide compound, a pharmaceutical composition, a preparation method and an application. Background technique [0002] Cancer is one of the major diseases that threaten human health. At present, the main treatment methods for cancer include drug therapy, surgical treatment, radiotherapy, etc., among which drug therapy is one of the most commonly used treatment methods. Traditional cytotoxic drugs cannot distinguish between tumor cells and normal cells, often causing serious side effects, while targeted drugs use tumor cells as specific targets, can accurately act on tumors, and can effectively improve the treatment level of cancer. Reduce the rate of adverse reactions. [0003] Isocitrate Dehydrogenase (IDH for short) family includes three members: IDH1 dependent on NADP (Nicotinamide Adenine Dinucleotide Phosphate, nicotinamide adenine dinucleot...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/04C07D401/14C07D403/14A61K31/506A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D401/14C07D403/04C07D403/14
Inventor 王永广黄巧萍万晓梦苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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